Despite the stunning success of many labs using Drosophila as a model for insect (and mammalian) innate immunity, we remain ignorant about (a) how components of the insect immune system are coordinated against infections of protozoan or metazoan parasites and, (b) how parasites resist, evade or thwart the host's defense responses. We are using a unique Drosophila-parasitic wasp model to answer both these questions. Leptopilina heterotoma (Lh) and L. boulardi (Lb) are both highly virulent parasitic wasps of D. melanogater that use different virulence strategies to overcome the host's immune responses. Host defenses include blood-cell mediated cellular and fat body-dependent humoral responses. Lh attacks the host's cellular immune system via virus-like particles (VLPs), whereas Lb, even though it produces VLPs, appears to confer virulence by alternate, but unknown mechanisms. The two wasp species also differ in their host range: Lh, a "generalist", can succeed on a wider range of host species than Lb, a "specialist" species. To identify the genes and pathways involved in larval defense against parasites, we infected Drosophila larvae with either Lb or Lh and compared the expression patterns of all genes. We found that (a) while Lbattacked larvae up-regulate many genes encoding recognition proteins and components of the Toll/NF-kB, JAK/STAT and melanization pathways, larvae attacked by Lh do not. These three pathways are genetically linked, although their site(s) of activation and the order in which they are activated are not clear, (b) Surprisingly, Lb-infected larvae activate humoral immunity as indicated by the strong activation of drosomycin, a specific target gene of the Toll pathway in the fat body. We propose that hemocytes play a central role in detecting infection and in coordinating the cellular and humoral arms of the immune response. We will test our "coordination model" by characterizing the expression patterns of specific signaling components identified in the microarray analysis in order to identify candidates, whose expression in larval hemocytes might regulate activation of humoral pathways in the fat body or in the hemolymph. Using mutants and immune response assays, we will also analyze functions of candidate molecules in the coordination of cellular and humoral immune responses. Our findings will advance understanding of other host-pathogen systems, especially those that impact human health.